Direct Synthesis of Nitriles from Aldehydes Using an O-Benzoyl

Letter pubs.acs.org/OrgLett

Direct Synthesis of Nitriles from Aldehydes Using an O‑Benzoyl Hydroxylamine (BHA) as the Nitrogen Source Xiao-De An and Shouyun Yu* State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China S Supporting Information *

ABSTRACT: The direct synthesis of nitriles from commercially available or easily prepared aldehydes has been achieved. O-(4CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes, which can be converted to a nitrile with the assistance of a Brønsted acid. Several aliphatic, aromatic, and α,β-unsaturated nitriles that contain different functional groups were prepared in high yields (up to 94% yield). This method has notable advantages, such as simple and mild conditions, high yields, and good functional group tolerance.

T

he cyano group is one of the most important functional groups, and it exists in many natural products and biologically active molecules.1 Furthermore, nitriles can be used as versatile building blocks in the synthesis of natural products, pharmaceuticals, agricultural chemicals, and dyes.2 Therefore, the development of efficient methods for nitrile preparation has attracted intense interest from synthetic chemists.3 Traditional methods for preparing nitriles, such as the Sandmeyer reaction,4 the Rosenmund−von Braun reaction,5 cyanide− halide exchange reactions,1b,6 and the dehydration of amides or oximes,7 generally involve complicated operations, heavy metal waste, toxic reagents (e.g., KCN or CuCN), or harsh reaction conditions (e.g., POCl3 and high temperature). In recent decades, aldehydes have been used as ideal synthetic precursors for nitriles due to their ready availability and ease of use.8−10 These methods suffer from limited substrate scope, complicated operations, and low functional group compatibility.8 Some strong oxidants are typically essential for the conversion of aldehydes to nitriles, which also lowers functional group tolerance.8,9 Therefore, the direct synthesis of nitriles from aldehydes under simple conditions with high functional group compatibility is still a synthetic challenge although it is highly useful.10,7k Additionally, the selection of the nitrogen source is crucial to this transformation. Very recently, we synthesized a series of substituted Obenzoyl hydroxylamines (BHAs), such as O-(4-cyanobenzoyl)hydroxylamine (CN-BHA, 1a) and O-(4-CF3-benzoyl)-hydroxylamine (CF3-BHA, 1b).11 These BHAs can serve as the nitrogen source for the conversion of aryl or vinyl aldehydes to aza-arenes under photoredox catalysis (Figure 1a).11b When the vinyl aldehyde 2, was subjected to the photocatalytic conditions via irradiation with white LEDs, the quinoline 3 was observed in a 34% NMR yield. Interestingly, the nitrile 4 was also produced in a 18% NMR yield (Figure 1b). Further © XXXX American Chemical Society

Figure 1. Serendipitous nitrile formation from an aldehyde and BHA.

experiments demonstrated that the photocatalyst and visible light irradiation were not necessary for conversion of the aldehyde 2 to the nitrile 4. Treatment of the aldehyde 2 with CN-BHA (1a) and p-Cl-benzenesulfonic acid (CBSA) without Received: September 3, 2015

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DOI: 10.1021/acs.orglett.5b02547 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

more inexpensive starting materials compared with CN-BHA, CF3-BHA was chosen for further investigation. After determining the optimized reaction conditions, the synthetic potential of this reaction was investigated, and the results are summarized in Schemes 1 and 2. First, a series of

a photocatalyst and visible light irradiation produced the nitrile product 4 in a 14% NMR yield, together with the O-acyl oxime 5 in a 58% NMR yield. These results imply that the direct synthesis of nitriles from aldehydes is feasible when BHA is used as the nitrogen source (Figure 1c). Next, we produced a general methodology to directly synthesize nitriles from aldehydes with BHA as the nitrogen source, based on this serendipitous discovery. The systematic condition screening began with the reaction of racemic citronellal ((±)-6a) with CF3-BHA (1b) to form the corresponding nitrile (±)-7a. When the solution of (±)-6a with 1b in DMF was stirred at room temperature without any additives, the desired nitrile (±)-7a was obtained in a 30% yield based on the 1H NMR analysis. The major side product, O-acyl oxime (±)-7a′, was obtained in a 60% yield (Table 1, entry 1).

Scheme 1. Conversion of Aliphatic Aldehydes to Nitrilesa

Table 1. Optimized Reaction Conditionsa

entry

additive

solvent

7a/%b

7a′/%b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19d

− CBSA CBSA CBSA CBSA CBSA CBSA CBSA CBSA CBSA CBSA CH3CO2H Cl3CCO2H PhSO3H PhCO2H p-CF3-PhCO2H TFA CSA CSA

DMF DMF DMA DMSO NMP MeOH EtOH DCM CH3CN toluene THF MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH

30 67 40 24 33 87 74 26 30 35 44 27 83 70 32 22 92 92(89c) 92

60 13 44 40 28 0 4 59 56 56 30 63 0 0 65 74 0 0 0

a

Reaction conditions: A mixture of 6 (0.2 mmol), 1b (0.24 mmol), and CSA (0.02 mmol, 10 mol %) in MeOH (2.0 mL) was stirred at rt. The yields are for the isolated products. bThe reaction was performed on a 8.0 mmol scale. cThe reaction temperature was 50 °C.

aliphatic aldehydes were tested (Scheme 1). Generally, acceptable to good isolated yields (51−91%) were obtained regardless of the functional groups on the aldehydes (7a−m). Different functional groups, such as a double bond (7a and 7e), a triple bond (7f), an ester (7d), an ether (7g), a lactam (7i), a hydroxyl group (7j), an amide (7k−7m), and a ketal (7m), tolerated these conditions. The steric effect affected this formation significantly, and bulky aldehydes, such as the Garner aldehyde, were converted to the corresponding nitrile 7m, but at an elevated temperature (50 °C). The dialdehyde also produced the dinitrile 7h in a good yield (91%) with 2.4 equiv of 1b. The reaction was scaled up to the gram scale (8 mmol) with a slightly lower yield (75%). We next explored the applicability of this strategy to aromatic aldehydes. The above established conditions were not applicable to aromatic aldehydes (only 23% yield of the desired aromatic nitrile was obtained even at 50 °C). However, after a slight modification, aromatic aldehydes could be also transformed into the corresponding nitriles in DME at 80 °C with the help of 30 mol % of TFA and using the same nitrogen source (for the condition optimization, see the Supporting Information). Satisfactory yields were achieved for a broad range of aromatic aldehydes under these modified conditions (Scheme 2a). Several aromatic nitriles (9a−9q) were prepared in 45−94% yields depending on the position and electronic properties of the substitutions on the benzene rings. Some sensitive functional groups, such as free phenol (9h) and ketone (9j), were compatible with this reaction. Heteroarenenitriles, such as indole (9m), pyrrole (9n), pyridine (9o),

a

Reaction conditions: A solution of (±)-6a (0.2 mmol), 1b (0.24 mmol), and an additive (0.02 mmol) in the indicated solvent (2.0 mL) was stirred at rt for 24 h. b1H NMR yield. cIsolated yield. dCN-BHA (1a) was used instead of 1b. CBSA = p-Cl-benzenesulfonic acid. CSA = L-(−)-camphorsulfonic acid.

The O-acyl oxime (±)-7a′ was converted to the nitrile, (±)-7a, with the help of a Brønsted acid (vide inf ra). A catalytic amount of CBSA (10 mol %) was added to the reaction mixture as an additive. A cleaner reaction was observed with a 67% yield of (±)-7a and a 13% yield of (±)-7a′ (entry 2). The solvent screening showed that protic solvents, such as MeOH and EtOH, are better solvents and gave 87% and 74% yields of the desired nitrile, respectively (entries 6 and 7). Then, the Brønsted acid was examined (entries 12−18). CSA and TFA were more suitable for this transformation with the same NMR yield (92% yield and 89% isolated yield for CSA). CN-BHA (1a) also served as the nitrogen source with an identical efficiency (entry 19). Because CF3-BHA can be prepared from B

DOI: 10.1021/acs.orglett.5b02547 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Conversion of Aromatic and α,β-Unsaturated Aldehydes to Nitrilesa

to demonstrate the practicability of this new method (Scheme 3). Commercially available spiramycin (10, 1.69 g) was treated Scheme 3. Gram Scale and Late-Stage Modification of Spiramycin

with 1b (1.5 equiv) and TFA (30 mol %) in DME at 80 °C to furnish the corresponding nitrile 11 (1.11 g) in a 66% yield without flash column chromatography. This strategy afforded a macrolide-based nitrile, which may possess biological activity. Additionally, the sensitive functional groups, such as olefin, tertiary amine, glucoside, lactone, and free hydroxyl, which are in the same molecule, are compatible with our method. Control experiments were conducted to determine the mechanism of this reaction (Figure 2a). Without the Brønsted

Figure 2. Mechanistic details. a

Reaction conditions: A mixture of 8 (0.2 mmol), 1b (0.3 mmol), and TFA (0.06 mmol, 30 mol %) in DME (2.0 mL) was stirred at 80 °C. The yields are for the isolated product. bThe corresponding aldehyde 8y was a 1:1 mixture of the E- and Z-isomers.

acid, the aldehyde 6a was fully converted into the O-acyl oxime 7a′ but only less than half of the O-acyl oxime 7a′ was converted into the nitrile 7a. The preformed O-acyl oxime 7a′ produced the nitrile 7a in an 86% NMR yield with the help of the Brønsted acid. We observed that almost no conversion of the preformed O-acyl oxime 7a′ to the nitrile 7a occurred in the absence of the Brønsted acid. Thus, a possible mechanism was proposed, as depicted in Figure 2b. First, an O-acyl oxime was generated from the aldehyde and CF3-BHA. The protonated Oacyl oxime produced a nitrile after losing a proton and a carboxylic acid. In summary, we have described a direct synthesis of nitriles from commercially available or easily prepared aldehydes. O-(4CF3-benzoyl)-hydroxylamine (CF3-BHA) was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes, which can be converted to a nitrile with the assistance of a Brønsted acid. Several functionalized aliphatic, aromatic, and α,β-unsaturated nitriles were prepared in high yields. The late-stage modification of spiramycin to the corresponding nitrile on a gram scale was also achieved in a satisfactory yield. The advantages, such as simple and mild

thiophene (9p), and ferrocene (9q), were also prepared using this method. The success with aliphatic and aromatic nitriles inspired us to explore the possibility of preparing more synthetically challenging α,β-unsaturated nitriles from α,β-unsaturated aldehydes using a similar strategy. To our delight, the identical conditions for aromatic aldehydes were applicable to α,βunsaturated aldehydes. Thus, a series of di- and trisubstituted α,β-unsaturated nitriles (9r−9z) were produced in 56−92% yields via this method (Scheme 2b). Notably, no Michael addition, which was often observed as a major side reaction in the synthesis of α,β-unsaturated nitriles from the corresponding aldehydes,10a was observed. A functional-group-enriched macrolide antibiotic, named spiramycin,12 which is widely used in clinics to treat toxoplasmosis and other soft tissue infections was employed C

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conditions, high yields, and good functional group tolerance, may lead to application of this method for the synthesis of nitriles.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b02547. Full experimental and characterization data for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the 863 program (2013AA092903), the National Natural Science Foundation of China (21272113, 81421091), and Qing Lan Project of Jiangsu Province is acknowledged.

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REFERENCES

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